The objective of the proposed research is identification of the mechanisms responsible for exercise vasodilation. The particular emphasis is on the mediator(s) responsible for steady state free flow exercise hyperemia. We propose to evaluate the roles of adenosine, ATP, NH4 ion, local neurogenic vasodilation, and prostaglandins. In addition, we propose to attempt to identify the mechanisms responsible for increased muscle blood flow in hyperthyroidism. We will use blood perfused canine skeletal muscles, as well as isolated arterial strips and skeletal muscle fiber bundles. We will use mathematical models to bridge the gap between in vitro and in vivo preparations. A unique feature of the proposed research is that we will combine pharmacologic interventions with actual measurements of transient and steady state changes in the suspected mediators during exercise. For example, we will combine tracer kinetic data, pharmacologic inhibition of cell uptake and deamination of adenosine, tissue measurements of adenosine, and mathematical modeling to determine whether it causes free flow exercise hypermia. Because it is likely that more than one mediator contributes to free flow exercise hyperemia, study of several potential mediators in the same preparation offers the opportunity to assign relative potencies to each of several mechanisms.